Proteinuria and Glomerular Disease PDF

Proteinuria and Glomerular Disease Please open Echo360 to participate in polls Jennifer M. Reinhart, DVM, PhD, DACVIM, DACVCP Assistant Professor, Small Animal Internal Medicine [email protected] Learning Objectives • Be able to localize proteinuria within the urinary tract • Be able to ident...

Proteinuria and Glomerular Disease Please open Echo360 to participate in polls Jennifer M. Reinhart, DVM, PhD, DACVIM, DACVCP Assistant Professor, Small Animal Internal Medicine [email protected] Learning Objectives • Be able to localize proteinuria within the urinary tract • Be able to identify the major primary glomerulopathies in cats and dogs • Be able to recommend initial diagnostics for a patient with glomerular proteinuria • Be able to recommend initial treatment for a patient with glomerular proteinuria Approach to Proteinuria Proteinuria • Def. – abnormal amount of protein in the urine Proteinuria Glomerular Basement Membrane • > 1 mg/dL • Pre-Renal • Renal Bowman’s Space • Kidney has mechanisms to prevent protein loss • Glomerulus filters proteins by Tubular Cells • Tubular • Glomerular • Post-Renal • Size • Charge Pre-Renal Proteinuria • Excess plasma proteins exceed resorption in proximal renal tubules • Usually, low molecular weight • Myoglobin • Para-proteins • Higher molecular weight proteins can seep through • Hemoglobin Tubular (Renal) Proteinuria Glomerular Basement Membrane Bowman’s Space Tubular Cells • Normal filtration, lack of resorption • Diseases affecting the proximal tubules • Inherited diseases – cystinuria, Fanconi syndrome • Tubulointerstitial disease • Leptospirosis • Chronic kidney disease • Toxins/drugs • Infiltrative neoplasia Glomerular Basement Membrane Bowman’s Space Tubular Cells Glomerular (Renal) Proteinuria Glomerular (Renal) Proteinuria Glomerular Basement Membrane • Abnormal filtration by the glomerulus Functional Glomerular Disease • “Leaky filter” • With mild to moderate disease, most leak is albumin and LMW proteins • Glomerular changes can be Bowman’s Space Tubular Cells • Functional (reversible) • Structural (irreversible) • Usually, extra-renal disease adversely affecting filtration • Hypertension • Cushing’s disease • Iatrogenic • Diabetes mellitus • Hyperlipidemia Structural Glomerular Disease*** aka glomerulopathy • Immune-complex glomerulonephritis (IGCN) • Glomerulosclerosis • Amyloidosis • Hereditary nephropathies Functional changes may progress to causing structural damage Post-Renal Proteinuria Glomerular Basement Membrane • Inflammation below the collecting duct • Infections, stones, neoplasia • Renal hilus, ureter, neoplasia, bladder, prostate, urethra, neoplasia Bowman’s Space • Extraurinary causes • Genital or perineal diseases Tubular Cells Inflammatory Proteins Glomerular Disease/ Glomerulopathies Glomerular Disease – Pathophysiology Glomerular Disease – Pathophysiology • Glomerulus is a specialized capillary bed • Glomerular filtration apparatus has three layers Immune-complex glomerulonephritis (ICGN) • Deposition of immune-complexes into the glomerular filtration apparatus • Sub-classified based on location of IC deposition • Fenestrated endothelium • Basement membrane • Visceral epithelium (podocytes) • • • • • • Glomerular diseases cause damage to filtration barrier • • • • • Immune-complex glomerulonephritis (ICGN) – 50% Glomerulosclerosis – 20% Amyloidosis – 15% Hereditary nephropathies Minimal change glomerulopathy • Clinically, we treat as one group – ICGN • Not enough evidence in veterinary literature to recommend different treatment based on sub-class Glomerular Disease – Pathophysiology Glomerular Disease – Pathophysiology Immune-complex glomerulonephritis (ICGN) • Systemic illnesses associated with ICGN Disease Type Examples Viral disease CAV-1, FeLV, FIV, FIP Vector-borne disease Anaplasma, Ehrlichia, Lyme, Bartonella, Babesia, hemotropic Mycoplasma, heartworm, Leishmania, Trypanosoma Fungal disease Blastomycosis, coccidiomycosis Chronic bacterial infection Endocarditis, diskospondylitis, pyoderma, pyometra, prostatitis Immune-mediated disease Systemic lupus erythematosus (SLE) Neoplasia Leukemia, lymphoma, systemic histiocytosis Membranous Membranoproliferative Proliferative Crescentic type IgA nephropathy Many times, we do not identify an underlying cause  idiopathic ICGN Glomerulosclerosis • Fibrous deposition/replacement of glomerulus • Focal or segmental • Pathology not well understood Amyloidosis • Deposition of abnormally folded proteins into glomerular filtration apparatus • In cats and dogs, usually serum amyloid A (sAA) amyloidosis • sAA is an acute phase protein – released during inflammation • Classic association is Shar Pei fever Glomerular Disease – Pathophysiology Complications of Glomerular Disease Hereditary Nephropathies • Rare, genetic conditions • Lack of production of glomerular basement collagen proteins Minimal Change Glomerulopathy • Abnormal podocyte foot processes • Very rare in cats and dogs Hypertension • RAAS activation from glomerular disease can cause hypertension • AngII  vasoconstriction • Aldosterone  Na retention  volume expansion Angiotensinogen ↓ GFR ↑ GFR • Common and relatively predictable • Clinical signs of end-organ damage • • • • Eye Brain Heart Kidney Renin Angiotensin I ACE Angiotensin II ↑ BP Aldosterone Na Retention Volume Expansion Complications of Glomerular Disease Complications of Glomerular Disease Hypercoagulability • Loss of low molecular weight anticoagulant factors Fluid Accumulation • Ascites, pleural effusion, tissue edema • Pathogenesis unclear • Possible contributing factors • E.g., anti-thrombin III • Thrombocytosis • Relatively uncommon and unpredictable • Clinical signs depend on location of clot • • • • Pulmonary thromboembolism – dyspnea Saddle thrombus – hind limb pain, dysfunction Ischemic encephalopathy – “stroke” Others • Hypoalbuminemia  low oncotic pressure • RAAS activation  fluid retention • Unknown vascular permeability factor  leaky vessels Complications of Glomerular Disease Glomerular Disease – Diagnosis Protein-Losing Nephropathy (PLN) • Hypoproteinemia (hypoalbuminemia) due to renal loss Nephrotic Syndrome • Components: • Dogs >> cats • Most common in middle-aged to older animals • • • • Proteinuria Hypoalbuminemia Hypercholesterolemia +/- Effusion/edema • Average age (dogs) – 8.3 yrs • Exception – hereditary nephropathies • Breed predispositions • Uncommon - ~15% of dogs with glomerular disease • Carries a poorer prognosis Ettinger & Feldman, 2017 Glomerular Disease – Diagnosis Glomerular Disease – Diagnosis • Clinical signs are variable Signs consistent with complications of glomerular disease/proteinuria • Thromboembolism – dyspnea (PTE), loss of limb function, CNS signs • Fluid retention – ascites, edema, pleural effusion • Hypertension – CNS signs, retinal detachment, HCM • Dependent on severity of proteinuria and presence/absence of azotemia • May be detected on routine health screenings • May manifest signs of underlying infectious, inflammatory, neoplastic disease (ICGN) • Non-specific signs – weight loss, lethargy, decreased appetite, vomiting • Signs consistent with CKD – PU/PD, uremic breath, oral ulcers, small to normal kidneys Glomerular Disease – Diagnosis Glomerular Disease – Diagnosis Proteinuria is the hallmark of glomerular disease Proteinuria is the hallmark of glomerular disease • Urine protein:creatinine ratio (UPC) • Dipstick/Urinalysis • The higher the UPC, the more likely proteinuria is glomerular in origin • Early glomerular disease may only have mild proteinuria • Screening test for proteinuria • Proteinuria is significant if • Requires serial monitoring • Concentrated urine: >= 2+ • Non-concentrated urine: any • Rule out pre- and post-renal causes of proteinuria • Establishes persistence • Up to 50% day to day variability • Consider pooled samples Glomerular Disease – Diagnosis Glomerular Disease – Diagnosis Urinalysis • Complete blood count • Proteinuria • Cylindruria • Proteinuria promotes precipitation • Usually, hyaline • Urine specific gravity • Depends on tubular function: • Disease only affecting the glomerulus – concentrated • Inflammation/fibrosis extending to the tubulointerstitium – dilute • Normocytic, normochromic anemia • If moderate to severe interstitial involvement • Thrombocytosis • Serum biochemistry profile • Hypoalbuminemia • Globulins usually normal • Azotemia/hyperphosphatemia • If CKD has progressed • Hyperlipidemia • Cholesterol and triglycerides • Not well understood Glomerular Disease – Diagnosis Glomerular Disease – Diagnosis • Blood Pressure • Infectious disease screening Advanced diagnostics – look for a cause • Thoracic radiographs • Abdominal ultrasound • More extensive infectious disease testing • Antinuclear antibody (SLE) Glomerular Disease – Diagnosis Proteinuria Knowledge Check #1 Advanced diagnostics – RENAL BIOPSY • Only way to distinguish between primary glomerular diseases A 6 yo FS Doberman Pinscher presents for severe ascites, which fluid analysis reveals to be a pure transudate. Based on the biochemistry panel, you suspect nephrotic syndrome. What diagnostic test is necessary to confirm your diagnosis? A) Urine protein:creatinine ratio B) Systolic blood pressure C) Renal biopsy D) Urine culture • Hypertension is common with proteinuria • Non-renal causes of hypertension can cause proteinuria • Serial monitoring to confirm • For common diseases in area that cause ICGN • 4DX – heartworm, Lyme, Anaplasma, Ehrlichia • ICGN vs. amyloid vs. glomerulosclerosis vs. other • Indicated when differentiating causes will impact treatment • Not needed in patients who respond to standard therapy for proteinuria • Avoid in patients with end-stage CKD • Send to a veterinary nephropathologist Biochem Panel Creat 3.8 mg/dL BUN 59 mg/dL P 4.9 mg/dL Alb 1.6 g/dL Glob 3.6 g/dL Chol 423 mg/dL RI 0.5-1.5 RI 6-30 RI 2.7-5.2 RI 2.5-3.8 RI 2.6-3.2 RI 129-297 Glomerular Disease Therapy Management of Proteinuria – Diet • Divided into two categories • Protein restriction • Standard therapy • Management of proteinuria • Management of complications • Therapy for underlying disease • Best chance of success – identify and treat underlying disease • Regardless of degree of azotemia • In contrast to non-proteinuric CKD • Decreases intraglomerular pressures, magnitude of proteinuria, and uremic toxins • PUFA Supplementation • Antioxidant effects • Many renal diets are already supplemented • Sodium restriction • Prevent excessive volume expansion Management of Proteinuria – RAAS Blockade Management of Proteinuria – RAAS Blockade • Proteinuria results from • Angiotensin Converting Enzyme Inhibitors (ACEi) • A damaged glomerular filtration membrane • Excess intraglomerular pressure from RAAS activation • AngII causes efferent arteriolar constriction • Block RAAS  • Dilate efferent arteriole  • Reduce intraglomerular pressure  • Reduce proteinuria • Inhibits AngII production • Benazepril or enalapril • Starting dose: 0.25 mg/kg BID • Angiotensin Receptor Blockers (ARBs) • Blocks AngII from binding its receptor • Telmisartan • Starting dose: 0.5 mg/kg SID • May be combined in refractory cases Management of Proteinuria – RAAS Blockade Management of Hypertension • Potential Adverse Effects of ACEi/ARB • Start with ACEi/ARBs (already on for proteinuria) • Decreases GFR • Care with severely azotemic patients (stage 4) • Hyperkalemia • Decreased GFR and indirect aldosterone inhibition • Dose reduction necessary when K+ > 6.0-6.5 mmol/L • Also can try dietary modification, potassium binders • Mild antihypertensives • May need more potent drugs • Calcium channel blockers – amlodipine • Direct vasodilator – hydralazine • See CKD lecture for more…. Management of Hypercoagulability Management of Fluid Accumulation • Antiplatelet drugs generally used • Thoracocentesis • Abdominocentesis? • Safe and easy to use • Clopidogrel 1 mg/kg/day • Aspirin 1-2 mg/kg/day • Anticoagulants? • Heparin and warfarin (higher risk of complications) • Factor Xa inhibitors – rivaroxaban, apixaban ($$) • When to initiate therapy? • Some vets start regardless • Some wait until hypoalbuminemic • Only enough to keep patient comfortable • Mild diuretics • Spironolactone • Hydrochlorothiazide • Monitor electrolytes closely! • Care with fluid therapy Treatment of Underlying Disease Monitoring of Glomerular Disease • If a non-renal cause of glomerular disease is present – treat! • Every 2-4 weeks initially • Then every ~3 months, if stable disease • Monitor: • Antimicrobials, immunosuppressives, chemotherapy • Treatment for primary glomerulopathies should be based on biopsy • ICGN • Immunosuppressive protocols are available – mycophenolate mofetil • Renal values, electrolytes, UPC, BP, PCV, fluid accumulation • Amyloidosis • Colchicine? • Glomerulosclerosis, hereditary nephropathy, others • No specific therapies Prognosis of Glomerular Disease Proteinuria Knowledge Check #2 • Negative prognostic indicators (in dogs) A 12 yo MC Cocker Spaniel is found to by proteinuric (UPC 3.2) and hypertensive (BP 170 mmHg) on routine geriatric panel. Which drug is most appropriate to prescribe? A) Amlodipine B) Hydralazine C) Spironolactone D) Telmisartan • Azotemia • Nephrotic syndrome • Histopathologic diagnosis also affects prognosis References • Vaden SL. Chapter 325: Glomerular Disease. Textbook of Veterinary Internal Medicine. Ettinger SJ, Feldman EC, Cote E, editors. 8th ed. 2017. • IRIS Consensus Clinical Practice Guidelines for Glomerular Disease in Dogs. J Vet Intern Med. 2013;27(S1):S1-S75. QUEST ONS?